Overview
Definition:
Tuberous sclerosis complex (TSC) is an autosomal dominant genetic disorder characterized by the development of hamartomas (benign tumors) in multiple organs, including the brain, skin, heart, lungs, kidneys, and eyes
It is caused by mutations in the TSC1 or TSC2 genes, which regulate the mammalian target of rapamycin (mTOR) pathway.
Epidemiology:
TSC has an estimated prevalence of 1 in 6,000 to 1 in 30,000 live births worldwide
It affects all ethnic groups and both sexes equally
Approximately two-thirds of cases are due to de novo mutations, while one-third are inherited in an autosomal dominant pattern.
Clinical Significance:
TSC is a multisystem disorder with significant morbidity and mortality, particularly due to neurological complications like intractable epilepsy and neurodevelopmental disabilities, as well as renal and cardiac involvement
Early diagnosis and management are crucial to improve long-term outcomes and quality of life for affected individuals.
Clinical Presentation
Seizures:
Seizures are the most common neurological manifestation, occurring in 80-90% of individuals with TSC
Onset is typically in infancy, with infantile spasms (West syndrome) being a common presentation
Other seizure types include focal seizures, generalized tonic-clonic seizures, and absence seizures
Seizures can be refractory to antiepileptic drugs.
Skin Findings:
Skin manifestations are nearly universal in TSC, often appearing in infancy or early childhood
These include hypopigmented macules (ash-leaf spots), angiofibromas (facial adenoma sebaceum), shagreen patches (thickened, leathery plaques typically over the lumbosacral area), periungual or subungual fibromas, and cafe-au-lait spots.
Diagnostic Criteria:
The diagnostic criteria for TSC are based on the presence of major and minor features
A definitive diagnosis is made with either: 1) Two major features, or 2) One major feature and at least two minor features
Major features include tubers in the brain, facial angiofibromas or forehead plaques, ungual or gingival fibromas, hypopigmented macules, cardiac rhabdomyomas, renal angiomyolipomas, etc
Minor features include bone cysts, cerebral white matter migration lines, gingival hyperplasia, hamartomatous polyps in the gastrointestinal tract, etc.
Diagnostic Approach
History Taking:
A detailed family history for TSC or unexplained developmental delay/seizures is crucial
Inquire about the onset and characteristics of seizures, developmental milestones, and any skin changes noticed by parents
History of cardiac murmurs, respiratory symptoms, or renal issues should also be elicited.
Physical Examination:
A thorough dermatological examination is essential to identify characteristic skin lesions, including careful inspection of the face, scalp, trunk, and extremities
Neurological examination should assess for focal neurological deficits, developmental delay, and signs suggestive of increased intracranial pressure
Auscultate for cardiac murmurs and assess for abdominal masses.
Investigations:
Neuroimaging: MRI of the brain is the gold standard for detecting cortical tubers and subependymal nodules
EEG is essential for characterizing seizure types and guiding antiepileptic drug therapy
Skin biopsy may be considered for ambiguous lesions
Genetic testing for TSC1 and TSC2 mutations can confirm the diagnosis
Renal ultrasound or CT for angiomyolipomas
Chest CT for lymphangioleiomyomatosis (LAM) in older females
Echocardiography for cardiac rhabdomyomas.
Differential Diagnosis:
Differential diagnoses for seizures in infancy include other causes of epilepsy such as pyridoxine deficiency, genetic epilepsies, metabolic disorders, and hypoxic-ischemic encephalopathy
Skin findings can overlap with neurofibromatosis, other phakomatoses, and benign nevi
Angiofibromas can be confused with acne or other facial lesions.
Management
Seizure Management:
Management focuses on controlling seizures, which often requires a multi-drug regimen
First-line agents include vigabatrin or ACTH for infantile spasms
Other antiepileptic drugs like levetiracetam, valproic acid, or topiramate are used for other seizure types
Ketogenic diet or vagus nerve stimulation may be considered for refractory epilepsy
Surgical resection of tubers may be an option in selected cases.
Skin Management:
Treatment of skin lesions is primarily cosmetic
Facial angiofibromas can be treated with topical or oral everolimus, laser therapy (pulsed dye laser), or surgical excision
Shagreen patches and hypopigmented macules typically do not require treatment
Subungual fibromas may require surgical excision if painful or causing nail deformity.
Systemic Management:
Management of other organ systems depends on the findings
Renal angiomyolipomas may require intervention if they are large or bleeding (e.g., embolization, surgical resection)
Cardiac rhabdomyomas often regress spontaneously but require monitoring
Pulmonary LAM may require mTOR inhibitors like sirolimus or everolimus.
Supportive Care:
Comprehensive care involves a multidisciplinary team including neurologists, dermatologists, geneticists, nephrologists, cardiologists, and developmental pediatricians
Early intervention services, educational support, and psychological support for patients and families are crucial for managing developmental delays and behavioral issues.
Complications
Neurological Complications:
Intractable epilepsy, intellectual disability, autism spectrum disorder, behavioral problems (ADHD, aggression), and hydrocephalus
Brain tumors (subependymal giant cell astrocytomas, SEGA) can also occur.
Renal Complications:
Renal angiomyolipomas (most common renal manifestation), renal cell carcinoma (rare), and chronic kidney disease
Hemorrhage from angiomyolipomas can be life-threatening.
Cardiac Complications:
Cardiac rhabdomyomas (most common cardiac manifestation in infants), which can cause arrhythmias or outflow tract obstruction
Heart failure is rare.
Pulmonary Complications:
Lymphangioleiomyomatosis (LAM) in adult females, leading to progressive dyspnea and pneumothorax
Pulmonary hemangiomas and cystic lung disease can also occur.
Prevention Strategies:
While TSC is a genetic disorder and cannot be prevented, early diagnosis and prompt management of seizures and other organ involvement can significantly reduce morbidity and improve outcomes
Genetic counseling is important for affected families.
Prognosis
Factors Affecting Prognosis:
Prognosis varies widely depending on the severity and extent of organ involvement
Individuals with less severe disease may have a near-normal lifespan and quality of life
Those with severe neurological involvement, intractable epilepsy, or significant organ dysfunction have a poorer prognosis.
Outcomes:
With optimal management, many individuals with TSC can lead fulfilling lives
However, significant challenges remain, particularly concerning epilepsy control, intellectual development, and the management of potential complications
Advances in mTOR inhibitors offer promising therapeutic options for various TSC-related manifestations.
Follow Up:
Lifelong, multidisciplinary follow-up is essential
This includes regular neurological assessments, EEG monitoring, dermatological evaluations, and periodic screening for renal, cardiac, and pulmonary involvement
Genetic counseling and support services are also vital.
Key Points
Exam Focus:
Remember the triad of seizures, intellectual disability, and skin manifestations in TSC
Infantile spasms are a critical early presentation
Recognize characteristic skin lesions: ash-leaf spots, angiofibromas, shagreen patches
Know the diagnostic criteria and the role of TSC1/TSC2 genes
mTOR pathway is a key therapeutic target.
Clinical Pearls:
Always consider TSC in infants with infantile spasms and skin findings
A detailed skin examination is as important as neurological assessment
Early aggressive seizure management is critical
Multidisciplinary care is paramount
Consider mTOR inhibitors (sirolimus, everolimus) for refractory seizures, SEGA, renal AMLs, and LAM.
Common Mistakes:
Underestimating the severity of epilepsy and its impact on neurodevelopment
Delaying appropriate imaging for brain tubers
Inadequate follow-up of renal angiomyolipomas
Confusing TSC with other phakomatoses without careful assessment of characteristic features
Not considering TSC in the presence of seemingly isolated skin findings in infancy.